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Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size: Inhibition of Matrix Metallopro...
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| Zeitschriftentitel: | Stroke |
|---|---|
| Personen und Körperschaften: | , , , , |
| In: | Stroke, 29, 1998, 5, S. 1020-1030 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Ovid Technologies (Wolters Kluwer Health)
|
| Schlagwörter: |
| author_facet |
Romanic, Anne M. White, Raymond F. Arleth, Anthony J. Ohlstein, Eliot H. Barone, Frank C. Romanic, Anne M. White, Raymond F. Arleth, Anthony J. Ohlstein, Eliot H. Barone, Frank C. |
|---|---|
| author |
Romanic, Anne M. White, Raymond F. Arleth, Anthony J. Ohlstein, Eliot H. Barone, Frank C. |
| spellingShingle |
Romanic, Anne M. White, Raymond F. Arleth, Anthony J. Ohlstein, Eliot H. Barone, Frank C. Stroke Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size Advanced and Specialized Nursing Cardiology and Cardiovascular Medicine Neurology (clinical) |
| author_sort |
romanic, anne m. |
| spelling |
Romanic, Anne M. White, Raymond F. Arleth, Anthony J. Ohlstein, Eliot H. Barone, Frank C. 0039-2499 1524-4628 Ovid Technologies (Wolters Kluwer Health) Advanced and Specialized Nursing Cardiology and Cardiovascular Medicine Neurology (clinical) http://dx.doi.org/10.1161/01.str.29.5.1020 <jats:p><jats:italic>Background and Purpose</jats:italic>—Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix and are implicated in numerous pathological conditions including atherosclerosis, inflammation, and tumor growth and metastasis. In the brain, the endothelial cell wall, strengthened by tight junctions, defines the blood-brain barrier (BBB). The extracellular matrix molecules constitute the basement membrane underlying the vasculature and play a critical role in maintaining the integrity of the BBB. After focal stroke, there is a breakdown of the BBB with an associated increase in vascular permeability, inflammatory cell influx, and neuronal cell death. The present study was designed to investigate the effects of MMP expression after stroke.</jats:p><jats:p><jats:italic>Methods</jats:italic>—Focal stroke was produced by permanent middle cerebral artery occlusion (MCAO) in the rat, and MMP protein expression was measured by Western blot and zymogram analysis over a time course ranging from 6 hours to 30 days (n=32). Immunohistochemistry at 1 and 5 days (n=8 and 6, respectively) was also utilized to characterize the expression of several MMPs and related proteins after stroke, including their cellular source. To test the hypothesis that early increased MMP-9 expression is involved in ischemic brain injury, a neutralizing monoclonal antibody directed against MMP-9 was administered intravenously (n=7 per group) 1 hour before MCAO, and infarct size was measured 24 hours later.</jats:p><jats:p><jats:italic>Results</jats:italic>—MMP expression increased progressively over time after stroke. After 12 hours, significant (<jats:italic>P</jats:italic><0.05) MMP-9 activity was observed that reached maximum levels by 24 hours (<jats:italic>P</jats:italic><0.001), then persisted for 5 days at this level and returned to basal (zero) levels by 15 days. On the basis of morphological criteria, MMP-9 appeared to stain with endothelial cells and neutrophils identified both within and at the periphery of the infarct within 24 hours of focal ischemia. After 5 days, MMP-9 appeared to stain with macrophages present within the infarcted brain. MMP-2 activity was significantly (<jats:italic>P</jats:italic><0.001) increased by 24 hours and was maximum after 5 days following MCAO. MMP-2 appeared to stain with macrophages present within the infarcted region. Unlike MMP-9 and MMP-2, tissue inhibitor of metalloproteinase-1 was identified at comparable levels in both control and ischemic tissue after MCAO. MMP-1 and MMP-3 could not be detected in the brain after focal stroke. When an MMP-9–neutralizing monoclonal antibody was administered systemically, animals exhibited significantly reduced infarct size (ie, a 30% reduction compared with non–immune antibody controls;<jats:italic>P</jats:italic><0.05).</jats:p><jats:p><jats:italic>Conclusions</jats:italic>—These results demonstrate that early increased MMP-9 expression in endothelial cells and infiltrating neutrophils is a significant response to cerebral focal ischemia and that selective inhibition of MMP-9 activity can significantly reduce brain injury after stroke.</jats:p> Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size Stroke |
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10.1161/01.str.29.5.1020 |
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Medizin |
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Ovid Technologies (Wolters Kluwer Health), 1998 |
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Ovid Technologies (Wolters Kluwer Health), 1998 |
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0039-2499 1524-4628 |
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1998 |
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Ovid Technologies (Wolters Kluwer Health) |
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ai |
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Stroke |
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49 |
| title_sub |
Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title |
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_unstemmed |
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_full |
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_fullStr |
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_full_unstemmed |
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_short |
Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_sort |
matrix metalloproteinase expression increases after cerebral focal ischemia in rats : inhibition of matrix metalloproteinase-9 reduces infarct size |
| topic |
Advanced and Specialized Nursing Cardiology and Cardiovascular Medicine Neurology (clinical) |
| url |
http://dx.doi.org/10.1161/01.str.29.5.1020 |
| publishDate |
1998 |
| physical |
1020-1030 |
| description |
<jats:p><jats:italic>Background and Purpose</jats:italic>—Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix and are implicated in numerous pathological conditions including atherosclerosis, inflammation, and tumor growth and metastasis. In the brain, the endothelial cell wall, strengthened by tight junctions, defines the blood-brain barrier (BBB). The extracellular matrix molecules constitute the basement membrane underlying the vasculature and play a critical role in maintaining the integrity of the BBB. After focal stroke, there is a breakdown of the BBB with an associated increase in vascular permeability, inflammatory cell influx, and neuronal cell death. The present study was designed to investigate the effects of MMP expression after stroke.</jats:p><jats:p><jats:italic>Methods</jats:italic>—Focal stroke was produced by permanent middle cerebral artery occlusion (MCAO) in the rat, and MMP protein expression was measured by Western blot and zymogram analysis over a time course ranging from 6 hours to 30 days (n=32). Immunohistochemistry at 1 and 5 days (n=8 and 6, respectively) was also utilized to characterize the expression of several MMPs and related proteins after stroke, including their cellular source. To test the hypothesis that early increased MMP-9 expression is involved in ischemic brain injury, a neutralizing monoclonal antibody directed against MMP-9 was administered intravenously (n=7 per group) 1 hour before MCAO, and infarct size was measured 24 hours later.</jats:p><jats:p><jats:italic>Results</jats:italic>—MMP expression increased progressively over time after stroke. After 12 hours, significant (<jats:italic>P</jats:italic><0.05) MMP-9 activity was observed that reached maximum levels by 24 hours (<jats:italic>P</jats:italic><0.001), then persisted for 5 days at this level and returned to basal (zero) levels by 15 days. On the basis of morphological criteria, MMP-9 appeared to stain with endothelial cells and neutrophils identified both within and at the periphery of the infarct within 24 hours of focal ischemia. After 5 days, MMP-9 appeared to stain with macrophages present within the infarcted brain. MMP-2 activity was significantly (<jats:italic>P</jats:italic><0.001) increased by 24 hours and was maximum after 5 days following MCAO. MMP-2 appeared to stain with macrophages present within the infarcted region. Unlike MMP-9 and MMP-2, tissue inhibitor of metalloproteinase-1 was identified at comparable levels in both control and ischemic tissue after MCAO. MMP-1 and MMP-3 could not be detected in the brain after focal stroke. When an MMP-9–neutralizing monoclonal antibody was administered systemically, animals exhibited significantly reduced infarct size (ie, a 30% reduction compared with non–immune antibody controls;<jats:italic>P</jats:italic><0.05).</jats:p><jats:p><jats:italic>Conclusions</jats:italic>—These results demonstrate that early increased MMP-9 expression in endothelial cells and infiltrating neutrophils is a significant response to cerebral focal ischemia and that selective inhibition of MMP-9 activity can significantly reduce brain injury after stroke.</jats:p> |
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| author | Romanic, Anne M., White, Raymond F., Arleth, Anthony J., Ohlstein, Eliot H., Barone, Frank C. |
| author_facet | Romanic, Anne M., White, Raymond F., Arleth, Anthony J., Ohlstein, Eliot H., Barone, Frank C., Romanic, Anne M., White, Raymond F., Arleth, Anthony J., Ohlstein, Eliot H., Barone, Frank C. |
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| description | <jats:p><jats:italic>Background and Purpose</jats:italic>—Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix and are implicated in numerous pathological conditions including atherosclerosis, inflammation, and tumor growth and metastasis. In the brain, the endothelial cell wall, strengthened by tight junctions, defines the blood-brain barrier (BBB). The extracellular matrix molecules constitute the basement membrane underlying the vasculature and play a critical role in maintaining the integrity of the BBB. After focal stroke, there is a breakdown of the BBB with an associated increase in vascular permeability, inflammatory cell influx, and neuronal cell death. The present study was designed to investigate the effects of MMP expression after stroke.</jats:p><jats:p><jats:italic>Methods</jats:italic>—Focal stroke was produced by permanent middle cerebral artery occlusion (MCAO) in the rat, and MMP protein expression was measured by Western blot and zymogram analysis over a time course ranging from 6 hours to 30 days (n=32). Immunohistochemistry at 1 and 5 days (n=8 and 6, respectively) was also utilized to characterize the expression of several MMPs and related proteins after stroke, including their cellular source. To test the hypothesis that early increased MMP-9 expression is involved in ischemic brain injury, a neutralizing monoclonal antibody directed against MMP-9 was administered intravenously (n=7 per group) 1 hour before MCAO, and infarct size was measured 24 hours later.</jats:p><jats:p><jats:italic>Results</jats:italic>—MMP expression increased progressively over time after stroke. After 12 hours, significant (<jats:italic>P</jats:italic><0.05) MMP-9 activity was observed that reached maximum levels by 24 hours (<jats:italic>P</jats:italic><0.001), then persisted for 5 days at this level and returned to basal (zero) levels by 15 days. On the basis of morphological criteria, MMP-9 appeared to stain with endothelial cells and neutrophils identified both within and at the periphery of the infarct within 24 hours of focal ischemia. After 5 days, MMP-9 appeared to stain with macrophages present within the infarcted brain. MMP-2 activity was significantly (<jats:italic>P</jats:italic><0.001) increased by 24 hours and was maximum after 5 days following MCAO. MMP-2 appeared to stain with macrophages present within the infarcted region. Unlike MMP-9 and MMP-2, tissue inhibitor of metalloproteinase-1 was identified at comparable levels in both control and ischemic tissue after MCAO. MMP-1 and MMP-3 could not be detected in the brain after focal stroke. When an MMP-9–neutralizing monoclonal antibody was administered systemically, animals exhibited significantly reduced infarct size (ie, a 30% reduction compared with non–immune antibody controls;<jats:italic>P</jats:italic><0.05).</jats:p><jats:p><jats:italic>Conclusions</jats:italic>—These results demonstrate that early increased MMP-9 expression in endothelial cells and infiltrating neutrophils is a significant response to cerebral focal ischemia and that selective inhibition of MMP-9 activity can significantly reduce brain injury after stroke.</jats:p> |
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| spelling | Romanic, Anne M. White, Raymond F. Arleth, Anthony J. Ohlstein, Eliot H. Barone, Frank C. 0039-2499 1524-4628 Ovid Technologies (Wolters Kluwer Health) Advanced and Specialized Nursing Cardiology and Cardiovascular Medicine Neurology (clinical) http://dx.doi.org/10.1161/01.str.29.5.1020 <jats:p><jats:italic>Background and Purpose</jats:italic>—Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the extracellular matrix and are implicated in numerous pathological conditions including atherosclerosis, inflammation, and tumor growth and metastasis. In the brain, the endothelial cell wall, strengthened by tight junctions, defines the blood-brain barrier (BBB). The extracellular matrix molecules constitute the basement membrane underlying the vasculature and play a critical role in maintaining the integrity of the BBB. After focal stroke, there is a breakdown of the BBB with an associated increase in vascular permeability, inflammatory cell influx, and neuronal cell death. The present study was designed to investigate the effects of MMP expression after stroke.</jats:p><jats:p><jats:italic>Methods</jats:italic>—Focal stroke was produced by permanent middle cerebral artery occlusion (MCAO) in the rat, and MMP protein expression was measured by Western blot and zymogram analysis over a time course ranging from 6 hours to 30 days (n=32). Immunohistochemistry at 1 and 5 days (n=8 and 6, respectively) was also utilized to characterize the expression of several MMPs and related proteins after stroke, including their cellular source. To test the hypothesis that early increased MMP-9 expression is involved in ischemic brain injury, a neutralizing monoclonal antibody directed against MMP-9 was administered intravenously (n=7 per group) 1 hour before MCAO, and infarct size was measured 24 hours later.</jats:p><jats:p><jats:italic>Results</jats:italic>—MMP expression increased progressively over time after stroke. After 12 hours, significant (<jats:italic>P</jats:italic><0.05) MMP-9 activity was observed that reached maximum levels by 24 hours (<jats:italic>P</jats:italic><0.001), then persisted for 5 days at this level and returned to basal (zero) levels by 15 days. On the basis of morphological criteria, MMP-9 appeared to stain with endothelial cells and neutrophils identified both within and at the periphery of the infarct within 24 hours of focal ischemia. After 5 days, MMP-9 appeared to stain with macrophages present within the infarcted brain. MMP-2 activity was significantly (<jats:italic>P</jats:italic><0.001) increased by 24 hours and was maximum after 5 days following MCAO. MMP-2 appeared to stain with macrophages present within the infarcted region. Unlike MMP-9 and MMP-2, tissue inhibitor of metalloproteinase-1 was identified at comparable levels in both control and ischemic tissue after MCAO. MMP-1 and MMP-3 could not be detected in the brain after focal stroke. When an MMP-9–neutralizing monoclonal antibody was administered systemically, animals exhibited significantly reduced infarct size (ie, a 30% reduction compared with non–immune antibody controls;<jats:italic>P</jats:italic><0.05).</jats:p><jats:p><jats:italic>Conclusions</jats:italic>—These results demonstrate that early increased MMP-9 expression in endothelial cells and infiltrating neutrophils is a significant response to cerebral focal ischemia and that selective inhibition of MMP-9 activity can significantly reduce brain injury after stroke.</jats:p> Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size Stroke |
| spellingShingle | Romanic, Anne M., White, Raymond F., Arleth, Anthony J., Ohlstein, Eliot H., Barone, Frank C., Stroke, Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size, Advanced and Specialized Nursing, Cardiology and Cardiovascular Medicine, Neurology (clinical) |
| title | Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_full | Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_fullStr | Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_full_unstemmed | Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_short | Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_sort | matrix metalloproteinase expression increases after cerebral focal ischemia in rats : inhibition of matrix metalloproteinase-9 reduces infarct size |
| title_sub | Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| title_unstemmed | Matrix Metalloproteinase Expression Increases After Cerebral Focal Ischemia in Rats : Inhibition of Matrix Metalloproteinase-9 Reduces Infarct Size |
| topic | Advanced and Specialized Nursing, Cardiology and Cardiovascular Medicine, Neurology (clinical) |
| url | http://dx.doi.org/10.1161/01.str.29.5.1020 |